WO2010037271A1 - 一组氨基苯酰衍生物及其制备方法和应用 - Google Patents

一组氨基苯酰衍生物及其制备方法和应用 Download PDF

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WO2010037271A1
WO2010037271A1 PCT/CN2009/001094 CN2009001094W WO2010037271A1 WO 2010037271 A1 WO2010037271 A1 WO 2010037271A1 CN 2009001094 W CN2009001094 W CN 2009001094W WO 2010037271 A1 WO2010037271 A1 WO 2010037271A1
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compound
och
preparation
amino
synthesis
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PCT/CN2009/001094
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English (en)
French (fr)
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蒋建东
余利岩
岑山
李卓荣
李艳萍
徐建
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中国医学科学院医药生物技术研究所
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Priority to EP09817185.3A priority Critical patent/EP2351731B1/en
Priority to CA2738256A priority patent/CA2738256A1/en
Priority to AU2009299062A priority patent/AU2009299062A1/en
Priority to JP2011528163A priority patent/JP2012503607A/ja
Priority to BRPI0913730A priority patent/BRPI0913730A2/pt
Priority to US12/998,210 priority patent/US8710098B2/en
Publication of WO2010037271A1 publication Critical patent/WO2010037271A1/zh
Priority to IL211864A priority patent/IL211864A0/en
Priority to ZA2011/03077A priority patent/ZA201103077B/en

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    • C07C327/28—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A—HUMAN NECESSITIES
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    • C07C233/43—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
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    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/76—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing nitrogen atoms, not being part of nitro or nitroso groups, bound to the carbon skeleton
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    • C07C311/08—Sulfonamides having sulfur atoms of sulfonamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07C311/38—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring having sulfur atoms of sulfonamide groups and amino groups bound to carbon atoms of six-membered rings of the same carbon skeleton
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    • C07C311/45—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups at least one of the singly-bound nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom, e.g. N-acylaminosulfonamides
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Definitions

  • the present invention relates to a group of aminobenzoyl derivatives; the invention further relates to a process for the preparation of said compounds and to their use in antiviral; the invention also relates to pharmaceutical compositions of said compounds. Background technique
  • antiviral drugs are targeted at viral proteins, and the mechanism of action is to inhibit viral replication or to block viral invasion.
  • the virus is a "mobile target” that relies on constant mutations to evade drug attacks.
  • Drugs targeting viral proteins have caused viral mutation and drug resistance, which has become a worldwide problem.
  • the current anti-HIV drugs commonly used in clinical practice are all HIV virus proteins. After long-term use, they will cause serious drug resistance problems, leading to treatment failure.
  • Multi-drug combination can greatly reduce the patient's viral load and slow down the drug resistance, but ultimately it is inevitable that drug resistance will occur; the newly-listed varieties will have certain advantages in anti-drug resistant strains, but with clinical use time The extension, resistance is still unavoidable. Therefore, dealing with viral resistance is the main issue to be solved.
  • the GA hypermutation of the HIV-1 genome, which inhibits viral replication, is a natural cytokine that is produced in the host cell.
  • the present invention confirmed that the 3-aminobenzoyl derivative has an effect of inhibiting hA3GMf-binding activity and inhibiting viral replication.
  • the compounds of the present invention and their effects have not been reported so far in related literatures at home and abroad. Developing targeted new drug targets The new antiviral compounds of hA3G are expected to make breakthroughs in solving the problem of HIV resistance, thus providing more effective new antiviral drugs for the clinic.
  • the main object of the present invention is to obtain a novel class of antiviral compounds and pharmaceutically acceptable salts targeting hA3G/Vif by the structure-activity study of a group of aminobenzoyl derivatives, which not only inhibit hA3G /Vif binds also has significant antiviral activity.
  • the present invention provides a group of amino substituted benzoyl derivatives.
  • the present invention provides a method of preparing the derivative.
  • the present invention provides a pharmaceutical composition containing such an aminobenzoyl derivative as an active ingredient.
  • the invention also provides the use of the aminobenzoyl derivative and a pharmaceutically acceptable salt in antiviral, especially in the treatment of HIV infection, including in combination with other antiviral chemotherapeutic drugs.
  • the present invention first provides an aminobenzoyl derivative having the following general formula (I) and a pharmaceutically acceptable salt -
  • R 3 may be the same or different, and represents: hydrogen, lower alkyl, carbonyl or sulfonyl;
  • Y stands for: C, S or so
  • R4 represents: hydrogen, lower hydrocarbon, hydroxy, aromatic or substituted arene
  • the amine-substituted benzoyl derivative of the formula (I) further comprises a product which undergoes salt-forming reaction with an acid.
  • the salt of the compound (I) with an acid may include inorganic acids such as hydrochloride, hydrobromide and sulfur. Acid salt, etc.; organic acid salts such as acetate, lactate, succinate, fumarate, maleate, citrate, benzoate, methanesulfonate and p-benzoate Wait.
  • aminobenzoyl derivatives defined in the screening of a large number of candidate compounds of the present invention may be exemplified by non-limiting structural examples:
  • the present invention further provides the 3-aminobenzoyl derivative or a salt thereof as an hA3G/Vif binding inhibitor and its use in the preparation of an antiviral drug.
  • an antiviral pharmaceutical composition comprising a therapeutically effective amount of the above 3-aminobenzoyl derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable pharmaceutical excipient, the compound itself Or a mixture thereof with a pharmaceutically acceptable excipient, diluent or the like is administered orally in the form of a tablet, a capsule, a granule, a powder or a saccharide, or is administered orally in the form of an injection.
  • compositions can be prepared by conventional pharmaceutical methods.
  • useful pharmaceutically acceptable adjuvants include excipients (e.g., saccharide derivatives such as lactose, sucrose, glucose, mannitol, and sorbitol; starch derivatives such as corn starch, potato starch, dextrin, and carboxymethyl starch; Cellulose derivatives such as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose; gum arabic; dextran; silicate derivatives such as magnesium metasilicate Aluminum; phosphate derivatives such as calcium phosphate; carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate, etc.; binders (eg, gelatin, polyvinylpyrrolidone, and polyethylene glycol); disintegrants ( For example, cellulose derivatives such as sodium carboxymethylcellulose, polyvinylpyrrolidone; lubricants (such as tal),
  • X 0, S or NH
  • the starting material 3-aminobenzoic acid (sulfonic acid), arylamine (phenol) or benzyl alcohol can be purchased or prepared by various known methods.
  • the invention also provides pharmacodynamic experimental studies of the compounds.
  • the present invention establishes a screening model for anti-HIV-1 drug ⁇ flux targeting Vij-mediated degradation of M3G, which can inhibit the degradation.
  • Process of small molecule active substances The model works by synthesizing HIV-1 Vif in cells and hA3G fused with yellow fluorescent protein (YFP). Due to the degradation of hA3G by Vif, the degradation of YFP fused on hA3G is caused. This results in a decrease in intracellular fluorescence intensity (530 nm). By measuring the change in fluorescence intensity, the effect of screening samples on Vif degradation of hA3G can be quantitatively analyzed.
  • YFP yellow fluorescent protein
  • the invention also establishes a screening model for detecting the degradation of P53 by the early gene product of adenovirus to ensure that the positive sample obtained by the model specifically blocks Vif degradation of hA3G. See Table 1 for the results.
  • the HIV-1 inhibitory activity of the inventive compound was determined using the HIV-1 P24 antigen kit, and the results are shown in Table 2. Upregulation activity of hA3G by the inventive compound
  • 1H should be R ( CDC1 3 , ⁇ ) 1.3 ( d, 3H, CH 3 ) , 4.5 (q, IH, CH), 3.8 (s, 9H, 4,, 5,, 6, OCH 3 ), 3.95 (s , 3H, 4-OCH 3 ), 6.44 (s, 2H, 2,, 6'-H), 6.98 (d, IH, 5-H), 7.76 (br, IH, NH), 7.9 (dd, IH, 6-H), 7.9(br, 2H, Li), 9.2(d, IH, 2-H)
  • the compound 84 was synthesized in a similar manner to Example 1 by condensation of 3-amino-4-methoxybenzenesulfonic acid, propionyl chloride and 3, 4, 5-trimethoxyphenol, yield 53%.
  • the compound 103 was obtained by the condensation of 3-amino-4-methoxybenzoic acid, methanesulfonyl chloride and 3, 4, 5-trimethoxyphenol in a similar manner to that of Example 1 to give a yield of 52%.
  • the synthesized compound further includes 11, 12, 14, 15, 17, 18, 19, 21, 22, 23, 24, 26, 27, 29, 30, 31, 33, 35, 46, 47, 50, 51, 52, 53, 57, 58, 59, 60, 62, 67, 70, 71, 72, 74, 76, 77, 78, 81, 82, 86, 88, 89, 92, 93, 94, 95, 96, 97, 99, 100, 101, 102, 104.
  • the synthesized compound further included 4, 6, 34, 36, 37, 41, 42, 43, 45, 54, 55, 56, 90.
  • 3-propionamido-4-methoxybenzoic acid 1.3 g was mixed with 10 ml of thionyl chloride and stirred at room temperature for 1 hour or more. Evaporate excess thionyl chloride, steam several times with toluene to ensure that the thionyl chloride is cleaned, the residue is dissolved in anhydrous ether, and an equivalent of 3, 4, 5-trimethoxy is added under ice cooling. The base cadmium is maintained at a temperature of 0 to -5 ° C for more than 1 hour. The reaction was treated according to a conventional method of the Grignard reaction to obtain 1.2 g (yield: 52%) of the objective compound (10).
  • the cells are cultured, and after the cells are overgrown, the old medium is discarded and digested with the digestive juice. After the cells are rounded, the digestive juice is discarded, the medium is immediately added, and the bottom of the bottle is gently blown with a pipette to completely separate the cells from the bottom of the bottle and disperse them into a single cell suspension. After counting the blood cell count plate, the cell suspension is inoculated into a culture dish for cell transfection. The medium containing the transfection plasmid and the transfection reagent was gently mixed, incubated at room temperature, added to the cell culture supernatant, and cultured for a while.
  • the old medium is aspirated, digested with the digestive juice, the digested solution is discarded, the medium is immediately added, and the cells are gently blown to disperse the cells into a single cell suspension. After the blood count plate counts, inoculate.
  • the diluent acts on the cell system.
  • test samples were added to the cell culture supernatant. After continuing the culture, the old medium was aspirated and the cells were pipetted with phosphate buffer (PBS) until the cells were completely detached.
  • PBS phosphate buffer
  • the cell suspension was transferred to a blackboard, and the fluorescence intensity was measured.
  • the excitation wavelength was ⁇ .485, and the detection wavelength was 520 nm.
  • the measurements were averaged twice.
  • the content of HIV-1 P24 antigen in the cell culture supernatant on the 4th day (96 hours) after the administration was measured, and the inhibitory activity of the drug against the virus was calculated. The results are shown in Table 2.

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Description

一组胺基苯酰衍生物及其制备方法和应用
技术领域
本发明涉及一组胺基苯酰衍生物； 本发明又涉及所述化合物的制备方法和 在抗病毒中的应用； 本发明还涉及所述化合物的药物组合物。 背景技术
目前， 临床上应用的抗病毒药物， 其作用靶点均为病毒蛋白， 作用机制为抑 制病毒的复制或阻断病毒的侵入。 病毒是 "移动的靶"， 依靠不断变异逃避药物 攻击。 以病毒蛋白为靶点的药物均造成病毒变异和耐药， 已成为世界性难题。 同 样， 目前临床常用的抗艾滋病病毒药物，其作用靶点均为 HIV病毒蛋白， 长期用 药后会产生严重耐药问題， 导致治疗失败。 多药联合应用（鸡尾酒疗法）可大大 降低患者病毒载量， 减缓耐药发生，但最终还是难免发生耐药； 新上市品种在抗 耐药毒株上会有一定优势， 但随着临床使用时间的延长， 耐药性还是无法避免。 因此， 对付病毒耐药是当前要解决的主要课题。
随着病毒学和细胞生物学研究的不断深入，大量研究成果表明，在生物进化 的漫长过程中，宿主细胞普遍形成针对不同病原病毒的防御体系，而病毒也会形 成特异性的拮抗机制，来实现对宿主细胞抑制作用的逃避。病毒和宿主细胞之间 相互依存和相互拮抗关系，特别是 HIV- 1相关细胞因子已经成为目前国际上医学 生物学基础和应用研究中最为前沿的方向和发展最为迅速的领域。
Vif (病毒感染性因子）是 HIV-1基因组编码的病毒蛋白， 在 HIV-1的复制 和感染过程中起着关键的作用。 近来的研究表明， hA3G与 Vif的生物学功能密 切相关。 M3G是在人的淋巴细胞中表达的一种 RNA/DNA编辑酶， 归属于 AP0BEC 蛋白超家族成员。 AP0BEC3G属于 AP0BEC家族， 最新的研究结果表明， 其可以导
'致 HIV- 1病毒基因组的 GA超突变， 髙效抑制病毒的复制， 是宿主细胞中天然产 生的抗艾滋病病毒的细胞因子。
在以 hA3G/Vif为靶点的抗病毒药物筛选研究中， 本发明证实， 3-胺基苯酰 衍生物具有抑制 hA3GMf结合活性， 并具有抑制病毒复制的作用。 本发明所述 化合物及其作用，迄今为止未见有国内外相关文献的报道。发展针对新药物靶点 hA3G的新型抗病毒化合物，对于解决 HIV耐药性问题可望取得突破性进展，从 而为临床提供更有效的新型抗病毒药物。
本发明的主要目的在于，通过对一组胺基苯酰衍生物的构效研究，筛选获得 一类新的以 hA3G/Vif 为靶点的抗病毒化合物及药用盐， 该类化合物不仅抑制 hA3G/Vif结合， 还具有显著的抗病毒活性。 发明内容
本发明提供了一组胺基取代苯甲酰衍生物。
本发明提供了制备所述衍生物的方法。
本发明提供了含有这种胺基苯酰衍生物作为活性成分的药物组合物。
本发明还提供了该胺基苯酰衍生物及药用盐在抗病毒中的应用，尤其是在 治疗 HIV感染中的应用， 包括与其它抗病毒化疗药物的联合应用。
本发明首先提供了具有以下通式 （I) 的胺基苯酰衍生物及药用盐-
Figure imgf000003_0001
(I)
其中：
代表： 氢， 连接于苯环的一个或多个硝基、 素、 氰基、 酯基、 酰胺基、 羟基、巯基、取代或未取代的低级烷基、低级烷氧基或芳基氧基、低级烷硫基或 芳基硫基、 氨基、 取代的氨基等；
， R3可以相同也可以不同， 代表： 氢， 低级烷基， 羰基或磺酰基；
X代表： 0、 S、 NH、 NR5、 CH2或 CHRe;
Y代表： C、 S或 so;
R4、 代表： 氢、 低级烃基、 羟基、 芳烃或取代的芳烃；
本发明按照上述定义通式 (I)的胺基取代苯酰衍生物还包括其与酸发生成盐 反应的产物。化合物 (I)与酸成盐的例子可以有无机酸， 如盐酸盐、氢溴酸盐和硫 酸盐等； 有机酸盐， 如乙酸盐、乳酸盐、 琥珀酸盐、 富马酸盐、 马来酸盐、 柠檬 酸盐、 苯甲酸盐、 甲磺酸盐和对苯甲酸盐等。
本发明从大量候选化合物筛选中所定义的胺基苯酰衍生物，其非限定性的结 构示例可以有：
Figure imgf000004_0001
Figure imgf000004_0002
Figure imgf000004_0003
Figure imgf000004_0004
Figure imgf000004_0005
Figure imgf000005_0001
Figure imgf000006_0001
Figure imgf000007_0001
Figure imgf000008_0001
Figure imgf000009_0001
Figure imgf000010_0001
Figure imgf000010_0002
2613 2611 2621 本发明进一步提供了该 3-胺基苯酰衍生物或其盐作为 hA3G/Vif结合抑制剂 及其在制备抗病毒药物中的应用。
本发明另一方面还提供了一种抗病毒药物组合物，其包括治疗有效量的上述 3-胺基苯酰衍生物或其药用盐及药学上可接受的药用辅料，可将化合物本身或其 与可药用赋形剂、稀释剂等的混合物以片剂、胶囊、颗粒剂、 散剂或糖 剂的形. 式口服给药， 或以注射剂的形式非口服给药。
上述制剂可通过常规制药方法制备。 可用的药用辅剂的例子包括赋形剂 (例如糖类衍生物如乳糖、 蔗糖、 葡萄糖、 甘露糖醇和山梨糖醇； 淀粉衍生物如 玉米淀粉、土豆淀粉、糊精和羧甲基淀粉； 纤维素衍生物如结晶纤维素、羟丙基 纤维素、 羧甲基纤维素、羧甲基纤维素钙、 羧甲基纤维素钠； 阿拉伯胶； 右旋糖 酐； 硅酸盐衍生物如偏硅酸镁铝； 磷酸盐衍生物如磷酸钙； 碳酸盐衍生物如碳酸 钙； 硫酸盐衍生物如硫酸钙等）； 粘合剂（例如明胶、 聚乙烯吡咯烷酮和聚乙 二醇）； 崩解剂（例如纤维素衍生物如羧甲基纤维素钠、聚乙烯吡咯烷酮）； 润 滑剂 （例如滑石、 硬脂酸钙、 硬脂酸镁、 鲸蜡、 硼酸、 苯甲酸钠、 亮氨酸）、 稳定剂 (对羟基苯甲酸甲酯、对羟基苯甲酸丙酯等);矫味剂 (例如常用的甜味剂、 酸味剂和香料等）； 稀释剂和注射液用溶剂（例如水、 乙醇和甘油等）。
本发明的 3-胺基苯酰衍生物及可药用盐可以根据目的化合物中的 X、 Y的结 构设计来确定起始物和反应物， 例如， 当 X=0、 S、 NH; Y=羰基、 磺酰基时， 各类 3-胺基苯酰衍生物可利用各类取代的 3-胺基苯甲酸（磺酸） 与芳基胺或酚 进行缩合反应制备， 具体过程可以是- 将保护的或酰化后的 A与 HOBT ( 1-羟基苯并三唑)， DIC (Ν， Ν'-二异丙 基碳二亚胺）按适当比例混合溶于 DMF (Ν, Ν-二甲基亚砜） 中， 大约半小时 后加入 Β室温下反应 24小时， 产物用柱层析分离纯化。
Figure imgf000011_0001
M: halogen or OH
A B (I) 其中，
X=0、 S或 NH;
Y=C、 S'或 SO;
Ri, R2, R3及 同前。 上述过程中， 起始原料 3-胺基苯甲酸（磺酸)、 芳基胺（酚）或苄基醇可以 购买或由各种已知方法制备。
发明还提供了所述化合物的药效学实验研究。
根据 HIV- 1病毒蛋白 Vif介导的 hA3G的降解作用的研究进展， 本发明建立 了以 Vif介导的降解 M3G为靶点的抗 HIV-1药物髙通量筛选模型， 以筛选能抑 制该降解过程的小分子活性物质。 这一模型的作用原理是， 在细胞内共表达 HIV-1的 Vif和融合了荧光蛋白 （yellow fluorescent protein (YFP) ) 的 hA3G, 由于 Vif对 hA3G的降解造成融合在 hA3G上的 YFP的降解，从而导致胞内荧光强 度 （530nm)的下降。 通过测定荧光强度的变化， 可以定量分析筛选样品对 Vif 降解 hA3G的影响。 同时为了区分样品对泛素降解途径的非特异性抑制作用， 本 发明还建立了检测以腺病毒早期基因产物对 P53的降解作用为复筛模型，以保证 该模型所得到的阳性样品特异性地阻断 Vif降解 hA3G。 结果参见表 1。
采用 HIV-1 P24抗原试剂盒， 测定了发明化合物的抑制 HIV-1 活性， 测定 结果见表 2。 发明化合物对 hA3G的上调活性
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发明化合物抑制 HIV-1活性
Figure imgf000016_0002
以上结果初步验证了本发明化合物或其药用盐在抑制 hA3G/Vif结合及抗病 毒方面的作用， 为其作为抗病毒药物的开发应用奠定了基础。
具体实施方式
以下实施例可以进一步帮助本领域技术人员了解本发明，但不以任何方式限 制本发明。
<实施例 1>、 (3-丙酰胺基 -4-甲氧基苯)甲酰 （3，， 4，， 5，-三甲氧基苯）胺（ l ) 的合成
在 25ml的烧瓶中， 将 0.6g 3-氨基 -4-甲氧基苯甲酸（1.0g， 6mmol)溶于干 燥的 THF (四氢呋喃）后， 加入三乙胺（1.2mU2mm0l)得到黄色透明溶液， 氮 气保护， 搅拌， 冰水浴条件下向其中滴加丙酰氯 （0.78ml,9mmol)， 滴加完毕后 自然恢复室温反应。 过滤反应液， 滤液蒸干后上硅胶柱分离得到 3-丙酰胺基 -4- 甲氧基苯甲酸 1.3g (收率 67%)。
将上述产物 lOOmg在冰水浴条件下与 HOBT 53mg (mmol), DIG 0.03ml (mmol)混合在干燥 DMF中， N2保护， 搅拌 30mi 后加入 3， 4, 5-三甲氧基苯 胺 72mg (mmol)， 自然恢复室温搅拌过夜。减压蒸干反应液， 残余物用乙酸乙酯 溶解后过滤， 滤液蒸干后用制备薄层硅胶板分离得到化合物 261 40mg (收率 30%)。
1H NMR (CDC13, δ) 1.3 (t, 3H, CH3)， 2.5(q, 2H, CH2), 3.82(s, 3H, 4，-OC¾), 3.9(s, 6H, 3',5'-OCH3), 3.95(s, 3H, 4-OCH3), 6.98(s, 2H, 2',6'-H), 7.0(d, 1H, 5-H)， 7.8(dd, 1H, 6-H), 7.9(br, 2H, NH), 8.9(d, 1H, 2-H)
<实施例 2>、 (3-丙酰胺基 -4-甲氧基苯） 甲酸 （3，， 4，， 5，-三甲氧基苯基）酯 (351 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 3， 4， 5-三甲氧基苯酚为原料， 按照 实施例 1的类似方法， 合成得到化合物 351， 两步收率 30%。
1H NMR(CDCl3,5)1.3(t, 3H, CH3), 2.5(q, 2H, CH2), 3.8 (s, 9H, 4，,5，,6，-OCH3), 3.95(s, 3H, 4-OCH3), 6.44(s, 2H, 2，,6，-H), 6.98(d, 1H, 5-H), 7.76(br, 1H, 3-NHCO), 7.9(dd, 1H, 6-H), 7.9(br, 1H, 1-CONH), 9.2(d, 1H, 2-H)
<实施例 3>、 (3-三氟乙酰胺基 -4-甲氧基苯） 甲酰 （3，， 4', 5，-三甲氧基苯基） 胺（263 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 三氟乙酰氯和 3， 4， 5-三甲氧基苯胺为原料， 按照实施例 1的类似方法， 合成得到化合物 263， 两步收率 50%。
1H NMR(CDCl3,6)3.84(s, 9H, 4，,5，，6，-OCH3), 4.0(s, 3H， 4-OCH3)， 6.97(s, 2H: 2，,6，-H), 7.03(d, 1H, 5-H), 7.86(d, 1H， 6-H), 7.9(s, 1H, 3-NHCOR), 8.6(s, 1H, 1-CONH ), 8.75(s, 1H, 2-H )
<实施例 4>、 (3-三氟乙酰胺基 -4-甲氧基苯） 甲酸（ 3，， 4，， 5，-三甲氧基苯基） 酯（353 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 三氟乙酰氯和 3， 4， 5-三甲氧基苯酚为原料， 按照实施例 1的类似方法， 合成得到化合物 353， 两步收率 40%。
1H NMR ( CDC13, δ ) 3.85(s, 9H, 4，,5，,6'-OCH3), 4.0(s, 3H, 4-OCH3), 6.46(s, 2H, 2',6'-H), 7.05(d, IH, 5-H), 8.07(dd, IH, 6-H), 8.54(s, 1H， 3-NHCOR), 9.12(s, IH, 2-H)
<实施例 5>、 ( 3-丙酰胺基 -4-甲氧基苯） 甲酰 （4'-氯苯）胺（2613 ) 的合成 以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 4-氯苯胺为原料， 按照实施例 1的类 似方法， 合成得到化合物 2613， 两步收率 30%。
1H NMR ( CDC13, δ ) 1.28 ( t, 3H, CH3 ) , 2.48(q, 2H, CH2), 3.96(s, 3H, 4，-OC¾),6.98(d,lH, 5-H), 7.33(d, 2H, 2，,6，-H), 7.6(d, 2H, 3，,5，-H), 7.77(dd, IH, 6-H), 7.8(s, IH, 3-NHCOR), 8.0(br,lH, 1-CONH ), 8.87(s,lH, 2-H)
<实施例 6>、 ( 3-丙酰胺基 -4-甲氧基苯） 甲酰（4' -甲氧基苯）胺（2611 ) 的合成 以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 4-甲氧基苯胺为原料， 按照实施例 1 的类似方法， 合成得到化合物 2611 , 两步收率 70%。
1H NMR( DMSO-d6, δ ) 1.07( t, 3H, CH3 ), 2.4(q, 2H, C¾), 3.73(s, 3H, 4'-OCH3), 3.89(s, 3H, 4-OCH3), 6.89(d, 2H, 2，,6，-H), 7.1(d,lH,5-H), 7.6(d, 2H, 3',5'-H), 7.7(dd,lH, 6-H), 8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 7>、 [3- (2-氯乙酰氨基） -4-甲氧基苯]甲酰（ 3，， 4，， 5'-三甲氧基苯） 胺（1 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 2-氯乙酰氯和 3， 4， 5-三甲氧基苯胺为原料， 按照实施例 1的类似方法， 合成得到化合物 1， 两步收率 56%。
1H NMR ( CDC13 , δ ) 4.5(s, 2H, CH2), 3.82(s, 3H, 4，-OCH3), 3.9(s, 6H, 3，，5，-OCH3), 3.95(s, 3H, 4-OCH3), 6.98(s, 2H, 2，，6'-H), 7.0(d, IH, 5-H), 7.8(dd, IH, 6-H), 7.9(br, 2H，丽)， 8.9(d, IH, 2-H)
<实施例 8>、 ( 3-丙酰胺基 -4-甲氧基苯） 甲酸（ 3' , 4， 5'-三甲氧基苯巯基） 酯 （9) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 3 '， 4' , 5， -三甲氧基苯硫酚为原料, 按照实施例 1的类似方法， 合成得到化合物 9, 收率 50%。
1H NMR ( CDC13 , δ ) 1.3 ( t, 3H, CH3 ) , 2.5(q, 2H, CH2), 3.8 (s, 9H, 4，,5，,6，-OCH3), 3.95(s, 3H, 4-OCH3), 6.44(s, 2H, 2，,6，-H), 6.98(d, IH, 5-H), 7.76(br, IH, NH), 7.9(dd, IH, 6-H), 7.9(br, 2H, NH), 9.2(d, IH, 2-H) <实施例 9>、 [3- (2-氟丙酰胺基） -4-甲氧基苯]甲酸 （3，， 4， 5，-三甲氧基苯巯 基）酯 （21 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 2-氟丙酰氯和 3'， 4'， 5， -三甲氧基苯硫酚为 原料， 按照实施例 1的类似方法， 合成得到化合物 21, 收率 54%。
1H應 R ( CDC13, δ ) 1.3 ( d, 3H, CH3 ) , 4.5(q, IH, CH), 3.8 (s, 9H, 4，,5，,6，-OCH3), 3.95(s, 3H, 4-OCH3), 6.44(s, 2H, 2，,6'-H), 6.98(d, IH, 5-H), 7.76(br, IH, NH), 7.9(dd, IH, 6-H), 7.9(br, 2H,丽)， 9.2(d, IH, 2-H)
<实施例 10>、 (3-甲氧基 -4-丙酰胺基苯）甲酰（3，， 4， 5，-三甲氧基苯）胺（64) 的合成
以 3-甲氧基 -4-氨基苯甲酸、 丙酰氯和 3 '， 4'， 5' -三甲氧基苯胺为原料， 按照实施例 1的类似方法， 合成得到化合物 64, 收率 57%。
1H NMR (CDC13) δ 1.3 (t, 3H, CH3) , 2.5(q, 2H, CH2), 3.82(s5 3H, 4，-OCH3)， 3.9(s, 6H, 3，,5，-OC¾), 3.95(s, 3H, 4-OCH3), 6.98(s, 2H, 2'56'-H), 7.0(d, IH, 2-H), 7.8(dd, IH, 6-H), 7.9(br, 2H, NH), 8.0(d, IH, 5-H)
<实施例 11>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰（4' -甲氧基呋喃 -2， -)胺（48) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 4-甲氧基呋喃 -2-胺为原料， 按照实施 例 1的类似方法， 合成得到化合物 48， 收率 70%。
1HNMR(DMSO-d6,5) 1.07(t, 3H, CH3), 2.4(q, 2H, CH2), 3.89(s, 3H, 4-OCH3), 4.73(s, 3H, 4，-OCH3), 6.89(s, IH, 5，-H), 7.6(d, IH, 5-H), 7.7(dd,lH, 6-H), 7.89(s, IH, 3，-H), 8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s3lH, 1-CONH)
<实施例 12>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰（4' -甲氧基吡咯 -2' -)胺（49) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 4-甲氧基吡咯 -2-胺为原料， 按照实施 例 1的类似方法， 合成得到化合物 49， 收率 68%。
1HNMR(DMSO-d6>6) 1.07(t, 3H, CH3), 2.4(q, 2H, CH2), 3.89(s, 3H, 4-OCH3), 4.73(s, 3H, 4，-OCH3), 6.76(s, IH, 5，-H)， 7.6(d, IH, 5-H), 7.7(dd,lH, 6-H), 7.72(s, 1H， 3，-H), 8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 13>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰- (嘧啶 4， -)胺（61 ) 的合成 以 3-氨基 -4-甲氧基苯甲酸、 丙酰氯和 4-氨基嘧啶为原料， 按照实施例 1的 类似方法， 合成得到化合物 61 , 收率 47%。
1H NMR(DMSO-d6,6) 1.07(t, 3H, CH3 ), 2.4(q, 2H, C¾), 3.89(s, 3H, 4-OCH3): 6.76(d, IH, 5'-H), 7.2(d, IH, 5-H), 7.6(d, IH, 5-H), 7.7(dd,lH, 6-H), 8.2 (s, IH, 3'-H); 8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 14>、 (2-丙酰胺基 -4-甲氧基苯）甲酰（3'， 4， 5'-三甲氧基苯）胺（63 ) 的合成
以 4-甲氧基 -2-氨基苯甲酸、 丙酰氯和 3 4'， 5， -三甲氧基苯胺为原料， 按照实施例 1的类似方法， 合成得到化合物 63， 收率 64%。
1H NMR (CDC13. δ) 1.3 (t, 3H, CH3 ) , 2.5(q, 2H, CH2), 3.82(s， 3H, 4，-OCH3), 3.9(s, 6H, 3',5，-OCH3), 3.95(s, 3H, 4-OCH3), 6.98(s, 2H, 2，,6，-H), 7.0(d, IH, 3-H), 7.8(dd, IH, 6-H), 7.9(br, 2H, NH), 8.0(d, IH, 5-H)
<实施例 15>、 (3-丙酰胺基 -4-甲基苯） 甲酰（4， -三氟甲氧基苯）胺（69) 的 合成
以 3-氨基 -4-甲基苯甲酸、丙酰氯和 4-三氟甲氧基苯胺为原料，按照实施例 1 的类似方法， 合成得到化合物 69， 收率 49%。
1H NMR (DMSO-d6, δ) 1.07 (t, 3H, CH3 ) , 2.4(q, 2H, CH2), 2.5(s, 3H, 4-CH3), 3.89(s, 3H, 4-OCH3), 6.89(d, 2H, 2',6'-H), 7.1(d,lH,5-H), 7.6(d, 2H, 3，,5'-H), 7.7(dd,lH, 6-H), 8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 16>、 (3-乙酰胺基 -5-三氟甲基苯） 甲酸 （3，， 4，， 5，-三甲氧基苯基) 酯 （73 ) 的合成
3-氨基 -5-三氟甲基苯甲酸、 乙酰氯和 3， 4， 5-三甲氧基苯酚为原料， 按照实 施例 1的类似方法操作， 合成得到化合物 73， 收率 61%。
1H NMR (CDC13, δ) 2.3 (s, 3H, CH3) , 3.8 (s, 9H, 4，,5，,6，-OC¾), 6.44(s, 2H, 2，,6，-H), 6.98(d, IH, 5-H), 7.76(br, IH, NH), 7.9(dd, IH, 6-H), 7.9(br, 2H, NH), 9.2(d, 1H， 2-H)
<实施例 17>、 (3-乙酰胺基 -4-氟 -5-甲氧基苯） 甲酰 （3，， 4，， 5，-三甲氧基苯) 胺（75) 的合成
以 3-氨基 -4-氟 -5-甲氧基苯甲酸、 丙酰氯和 3， 4， 5-三甲氧基苯胺为原料， 按照实施例 1的类似方法操作， 合成得到化合物 75， 收率 76%。
1HNMR (CDC13, 6) 2.3 (s, 3H, CH3) , 3.8 (s， 9H, 4，,5，,6'-OCH3), 3.97(s， 3H, 5-OCH3),6.44(s, 2H, 2，,6，-H), 7.76(br, IH, NH), 7.9(d, IH, 6-H), 7.9(br,lH, NH), 9.2(d, IH, 2-H)
<实施例 18>、 (3-丙酰胺基 -4-甲氧基 -6-氟苯） 甲酰 （3，， 4，， 5，-三甲氧基苯） 胺 （79) 的合成
以 3-氨基 -4-甲氧基 -6-氟苯甲酸、 丙酰氯和 3， 4, 5-三甲氧基苯胺为原料， 按照实施例 1的类似方法操作， 合成得到化合物 79， 收率 66%。
1H NMR (CDC13, δ) 1.07 (t, 3H, CH3) ,2.3 (q, 2H, CH2) , 3.8 (s, 9H, 4，，5，,6，-OCH3), 3.97(s, 3H， 4-OC¾),6.44(s, 2H, 2',6'-H), 7.76(br, IH, NH), 7.9(s， IH, 5-H), 7.9(br, IH, NH), 9.2(s, IH, 2-H)
<实施例 19>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰（3'-氟 -4， -胺基苯）胺（80) 的合成
以 3-氨基 -4-甲氧基苯甲酸、丙酰氯和 3-氟 -1， 4-苯二胺为原料， 按照实施例 1的类似方法操作， 合成得到化合物 80， 收率 60%。
1H NMR (CDC13> δ) 1.07 (t, 3H, CH3) , 2.4(q, 2H, C¾), 3.89(s, 3H, 4-OCH3), 6.89(d, 2H, 2，,6'-H), 7.1(d,lH,5-H), 7.6(d, IH, 5，-H), 7.7(dd,lH, 6-H), 8.3(d， IH, 6，- H),8.48(br,lH, 3-NHCOR), 9.15(s,lH, 2-H), 9.3(s,lH, 2，-H), 10.0(s,lH, 1-CONH) <实施例 20>、 (3-丙酰胺基 -4-甲氧基苯）磺酰（3'， 4' 5' -三甲氧基苯）胺（83) 的合成
以 3-氨基 -4-甲氧基苯磺酸、 丙酰氯和 3， 4， 5-三甲氧基苯胺为原料， 按照 实施例 1的类似方法操作， 合成得到化合物 83， 收率 63%。
1H NMR (DMSO-d6, δ) 1.03 (t, 3H， CH3) , 2.5(q, 2H, CH2), 3.8 (s, 9H, 4，,5，,6，-OCH3), 3.95(s, 3H, 4-OC¾)， 6.7(s, 2H, 2，,6，-H), 7.3(d, IH, 5-H), 7.7(br, IH, CO H)7.9(dd, IH, 6-H), 8.8(br, IH, S02NH), 9.2(d, IH, 2-H)。
<实施例 21>、 (3-丙酰胺基 -4-甲氧基苯）磺酸 （3，， 4' 5， -三甲氧基苯基） 酯 （84) 的合成
以 3-氨基 -4-甲氧基苯磺酸、 丙酰氯和 3, 4， 5-三甲氧基苯酚缩合， 按照实 施例 1的类似方法操作， 合成得到化合物 84， 收率 53%。 Ή NMR ( CDCI3, δ) 1.03 (t, 3H, CH3 ) , 2.5(q, 2H, CH2), 3.8 (s, 9H, 4，,5',6，-OCH3)， 3.95(s, 3H, 4-OCH3), 6.7(s, 2H, 2，,6，-H), 7.3(d, IH, 5-H), 7.7(br, 1H， CONH)7.9(dd, IH, 6-H), 9.2(d, IH, 2-H)
<实施例 22>、 (3% 4，， 5， -三甲氧基苯）磺酰（3-丙酰胺基 -4-甲氧基苯）胺 (91 ) 的合成
以 3-丙酰胺基 -4-甲氧基苯胺和 3， 4， 5-三甲氧基苯磺酸为原料， 按照实施 例 1的类似方法操作， 合成得到化合物 91, 收率 40%。
1HNMR (DMSO-d6, δ) 1.03 (t, 3H, CH3) , 2.5(q, 2H, CH2), 3.8 (s, 9H, 3，,4，,5， -OCH3), 3.95(s, 3H, 4-OCH3), 6.3(d, IH, 6-H), 6.7(br, IH, CONH)6.9(dd, IH, 5-H), 7.7(s, 2H， 2',6'-H), 8.8(br, IH, S02NH), 9.2(d, IH, 2-H)
<实施例 23>、 (3-甲磺酰胺基 -4-甲氧基苯） 甲酸（3'， 4'， 5' -三甲氧基苯基） 酯 （103) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 甲磺酰氯和 3， 4， 5-三甲氧基苯酚缩合， 按照 实施例 1的类似方法操作， 合成得到化合物 103， 收率 52%。
1H MR(DMSO-d6, δ) 2.5(s, 3H， CH3)， 3.8 (s, 9H, 3，,4，,5， -OCH3), 3.95(s, 3H,
4- OCH3), 6.7(s, 2H, 2',6'-H), 7.3(d, IH, 5-H), 7.7(br, IH, CONH)7.9(dd, IH, 6-H), 9.2(d, IH, 2-H)
<实施例 24>、 (3-三氟乙酰胺基 -4-甲氧基苯） 甲酸 （3，， 4，， 5，-三甲氧基苯基） 酯 （353) 的合成
以 3-氨基 -4-甲氧基苯甲酸、三氟乙酰氯和 3， 4， 5-三甲氧基苯酚为原料，按 照实施例 1的类似方法， 合成得到化合物 353， 两步收率 46%。
1HNMR(CDC13,5) 3.8 (s， 9H, 3，,4，,5， -OCH3), 6.44(s, 2H, 2',6，-H), 6.98(d, 1H:
5- H), 7.76(br, IH, NH), 7.9(dd, IH, 6-H), 9.2(d, IH, 2-H)
<实施例 25>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰（ 4'-硝基苯） 胺（2612) 的合成 以 3-氨基 -4-甲氧基苯甲酸、丙酰氯和 4-硝基苯胺为原料，按照实施例 1的类 似方法， 合成得到化合物 2612， 收率 53%。
1H NMR (DMSO-d6, δ) 1.07 (t, 3H, CH3) , 2.4(q5 2H, CH2), 3.73(s, 3H, 4'-OCH3), 3.89(s, 3H, 4-OC¾), 6.89(d, 2H, 2，,6，-H), 7.1(d,lH,5-H), 7.7(dd,lH, 6-H): 8.3(d, 2H, 3',5'-H),8.48(br,lH5 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s,lH, 1-CONH) <实施例 26>、 (3-丙酰胺基 -4-甲氧基苯） 甲酰（4'-氯苯）胺 （2613) 的合成 以 3-氨基 -4-甲氧基苯甲酸、丙酰氯和 4-氯苯胺为原料，按照实施例 1的类似 方法， 合成得到化合物 2613， 收率 56%。
1H NMR (DMSO-d6, δ) 1.07 (t， 3H, CH3) , 2.4(q, 2H, CH2), 3.73(s, 3H, 4'-OCH3), 3.89(s, 3H, 4-OCH3), 6.6(d, 2H, 2',6'-H), 7.1(d,lH,5-H), 7.7(dd,lH, 6-H), 8.2(d, 2H, 3，,5，-H),8.48(br,lH， 3-NHCOR), 9.15(s,lH, 2-H), 10.0(s5lH, 1-CONH) <实施例 27>、 (3-睛基 -4-甲氧基苯） 甲酰（3'， 4% 5'-三甲氧基苯）胺（68) 的合成
以 3-睛基 _4_甲氧基苯甲酸和 3， 4， 5-三甲氧基苯胺为原料， 按照实施例 1 的类似方法， 合成得到化合物 68， 收率 60%。
1HNMR (CDC13, δ) 3.82(s, 3H, 4'-OCH3), 3.9(s, 6H, 3，,5，-OCH3), 3.95(s, 3H, 4-OC¾), 6.68(s, 2H, 2，,6，-H), 6.8(d, 1H, 5-H), 7.0(dd, 1H, 6-H), 7.9(br, 2H, NH), 8.9(d, 1H, 2-H)
按照实施例 1的类似方法， 合成得到的化合物还包括 11、 12、 14、 15、 17、 18、 19、 21、 22、 23、 24、 26、 27、 29、 30、 31、 33、 35、 46、 47、 50、 51、 52、 53、 57、 58、 59、 60、 62、 67、 70、 71、 72、 74、 76、 77、 78、 81、 82、 86、 88、 89、 92、 93、 94、 95、 96、 97、 99、 100、 101、 102、 104。
〈实施例 28>、 (3-氨基 -4-甲氧基苯） 甲酰（3'， 4% 5'-三甲氧基苯）胺 (262) 的合成
1 )将 1.0g(6mmol)3-氨基 -4-甲氧基苯甲酸溶于 10ml的 4NNaOH水溶液中， 向其中缓慢滴加 2.5ml (llmmol) 叔丁酸酐,加热至 50°C反应至完全， 将碱水液 用 1N的盐酸快速酸化至 Ph=2,用氯仿提取三次， 合并氯仿液， 无水硫酸钠干燥 后浓縮蒸干得到的类白色固体 0.8g， 收率 50%。
2)将 1 ) 的产物 200mg (0.8mmol)在冰水浴条件下与 120mg (0.9mmol) HOBT, 0.06ml (0.6mmol) DIC混合在干燥 DMF中， N2保护， 搅拌 30min后加 入 160mg(0.9mmol)3， 4， 5-三甲氧基苯胺， 自然恢复室温搅拌过夜。 减压蒸干 反应液，残余物用乙酸乙酯溶解后过滤，滤液蒸干后用制备薄层硅胶板分离得到 产物 180mg,收率 55. 6%。
3)将 2) 的产物 160mg的溶于 6ml甲醇， 向其中滴加乙酰氯 0.12ml， 室温 反应至完全脱去叔丁酰保护基， 蒸干反应液后， 残余物用二氯甲烷 10ml混匀后 过滤得到白色固体（262) 60mg ， 收率 49%。
1H NMR (DMSO-d6, δ) 3.62(s, 3H, 4，-OCH3), 3.78(s, 6H， 3',5'-OCH3), 3.95(s, 3H, 4-OCH3), 4.5(br, 2H, -NH2), 7.1(d, IH, 5-H), 7.2(s, 2H, 2，,6，-H), 7.6(s, 1H， 6-H), 7.7(s, IH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 29>、 (3-氨基 -4-甲氧基苯） 甲酰苯胺 （2621 ) 的合成
以 3-氨基 -4-甲氧基苯甲酸和苯胺为原料， 按照实施例 28的类似方法， 合成 得到化合物 2621， 收率 37%。
1H NMR (DMSO-d6, δ) 3.55(s, 3H, 4-OCH3), 4.5(br, 2H, -NH2), 7.0(m, IH, 4，-H),7.1(d, IH, 5-H), 7.2(d, 2H, 2，,6，-H), 7.4(dd, 2H, 3',5'-H), 7.6(d, IH, 6-H), 7.7(s: IH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 30>、 (3-甲胺基 -4-甲氧基苯） 甲酰（3，-氟 -4， -磺胺基苯）胺 （98) 的合成
以 3-甲胺基 -4-甲氧基苯甲酸和 3-氟 -4-磺胺基苯胺为原料，按照实施例 28的 类似方法操作， 合成得到化合物 98， 收率 52%。
1H NMR (DMSO-d6, δ) 2.5(br, 2H, -NH2), 2.8(d, 3H, 3-CH3), 3.75(s, 3H, 4-OCH3), 4.5(br, IH, 3-NH), 6.5(m, IH, 6，-H), 6.67(s,lH, 2，-H), 6.8(d,lH, 5-H), 7.2(d, IH, 5，-H), 7.4(dd, 2H, 3',5'-H), 7.6(d, IH, 6-H), 7.7(s， IH, 2-H), 10.0(s,lH, 1-CONH)
<实施例 31>、 (3-甲胺基 -4-羟基苯）甲酰（ 2，， 6，-二甲氧基嘧啶 -4' -)胺（3 ) 的合成
以 3-甲胺基 -4-轻基苯甲酸和 2， 6-二甲氧基 4-氨基嘧啶为原料， 按照实施例 28的类似方法， 合成得到化合物 3， 收率 67%。
1H NMR (DMSO-de, δ) 2.8(d， 3H, 3-CH3), 3.73(s, 3H, 6，-OCH3), 3.77(s, 3H， 2'-OCH3), 4.4(br, IH, 3-NH), 5.1(br, IH, 4-OH), 6.8(d,lH, 5-H), 7.2(d, IH, 5，-H), 7.6(d, IH, 6-H), 7.7(s, IH, 2-H), 9.2(s,lH, 1-CONH)
<实施例 32>、 (3-氨基 -4-甲氧基苯） 甲酸 （3，， 4，， 5，-三甲氧基苯巯基） 酯 (5) 的合成
以 3-氨基 -4-甲氧基苯甲酸和 3, 4， 5-三甲氧基苯硫酚为原料， 按照实施例 28的类似方法， 合成得到化合物 5， 收率 47%。
1H NMR (DMSO-d6, 6) 3.62(s, 3H, 4'-OCH3), 3.78(s, 6H, 3，,5，-OC¾), 3.95(s, 3H, 4-OCH3), 4.2(br, 2H, -丽 2), 7.1(d， IH, 5-H), 7.3(s, 2H, 2，,6，-H)， 7.6(s, IH, 6-H), 7.7(s, IH, 2-H)
<实施例 33>、 (3-甲胺基 -4-甲氧基苯） 甲酰（ 3， 5-二甲氧基苯）胺（40) 的 合成
以 3-甲胺基 -4-甲氧基苯甲酸和 3， 5-二甲氧基苯胺为原料， 按照实施例 28 的类似方法， 合成得到化合物 40， 收率 50%。
1H NMR ( DMSO-d6, δ ) 2.4(d, 3H, 3-C¾), 3.75(s， 3H, 4-OCH3), 3.8(s, 6H，3，,5，-OCH3),5.0(br， IH, 3-NH), 6.5(s, 2H, 2，,6，-H), 6.8(d,lH, 5-H), 7.6(d, IH, 6-H), 7.7(s, IH, 2-H), 9.4(s,lH, 1-CONH)
<实施例 34>、 (3:氨基 -4-甲氧基苯）磺酰 （3， 4， 5-二甲氧基苯）胺（85) 的合成
以 3-氨基 -4-甲氧基苯磺酸和 3， 4， 5-二甲氧基苯胺为原料， 按照实施例 28 的类似方法， 合成得到化合物 85， 收率 52%。
1H NMR (DMSO-d6) δ 3.62(s, 9H, 3，,4，,5，-OCH3), 3.78(s, 3H, 4-OCH3), 4.2(br, 2H, -NH2), 7.1(d, IH, 5-H), 7.3(s, 2H, 2，,6，-H), 7.6(s， IH, 6-H), 7.7(s, 1H， 2-H), 8.5(br,lH,-S02NH)
<实施例 35>、 (3-羟基 -4-甲氧基苯）甲酰 （3，， ' , 5' -三甲氧基苯）胺（87) 的合成
以 3-羟基 -4-甲氧基苯甲酸和 3， 4， 5-二甲氧基苯胺为原料， 按照实施例 28 的类似方法， 合成得到化合物 87， 收率 34%。
1H NMR(DMSO-d6, δ) 3.62(s5 9H, 3，,4，,5，-OCH3), 3.78(s, 3H, 4-OCH3), 5.2(br, 1H， -OH), 7.1(d, IH, 5-H), 7.3 (s, 2H, 2，,6，-H), 7.6(s, IH, 6-H), 7.7(s, IH, 2-H), 8.9(br,lH,-CONH)
<实施例 36>、 (3-氨基 -4-甲氧基苯）甲酸 （3，， 4，， 5，-三甲氧基苯基）酯（352) 的合成
以 3-氨基 -4-甲氧基苯甲酸和 3， 4, 5-三甲氧基苯酚为原料， 按照实施例 28 的类似方法操作， 合成得到化合物 352， 收率 30%。 1HNMR (DMSO-d6, δ) 3.65(s, 3H, 4，-OCH3), 3.75(s, 6H, 3',5'-OCH3), 3.85(s, 3H, 4-OCH3), 5.05(br, 2H， -NH2), 6.56(s, 2H, 2，,6，-H), 6.94(d, IH, 5-H), 7.35(d, IH, 6-H), 7.38(s，lH, 2-H)
按照实施例 28的类似方法， 合成得到的化合物还包括 4、 6、 34、 36、 37、 41、 42、 43、 45、 54、 55、 56、 90。
<实施例 37>、 (3-丙酰胺基 -4-甲氧苯基） （3，， 4，， 5，-三甲氧基苄基）酮（10) 的合成
在 25ml的烧瓶中将 0.6g 3-氨基 -4-甲氧基苯甲酸 （1.0g， 6mmol)溶于干燥 的四氢呋喃后， 加入三乙胺（1.2ml,12mmol)得到黄色透明溶液， 氮气保护， 搅 拌， 冰水浴条件下向其中滴加丙酰氯 （0.78ml,9mmoD， 滴加完毕后自然恢复室 温反应。 过滤反应液， 滤液蒸干后上硅胶柱分离得到 3-丙酰胺基 -4-甲氧基苯甲 酸 1.3g。
3-丙酰胺基 -4-甲氧基苯甲酸 1.3g与 10ml二氯亚砜混合，并于室温下搅拌 1 小时以上。蒸除过量的二氯亚砜，用甲苯带蒸数次以保证二氯亚砜除干净，残余 物溶于无水乙醚中， 冰水冷却下加入等当量的 3, 4， 5-三甲氧基节基镉， 维持温 度在 0~-5°C反应 1小时以上。 按照格氏反应的常规方法处理反应， 得目标化合 物物（10 ) 1.2g (收率 52%)。
1H NMR (CDC13. δ) 1.03 (t, 3H, CH3) , 2.5(q, 2H, CH2), 3.4(s,2H,-COCH2), 3.8 (s, 9H, 4，，5',6，-OCH3), 3.95(s, 3H, 4-OCH3), 6.7(s, 2H, 2，,6，-H)， 7.3 (d, IH, 5-H), 7.4(s,lH,3-NHCO), 7.9(dd, IH, 6-H), 8.4(s,lH5l-CONH), 9.2(s, IH, 2-H)
<实施例 38>、 [3- (2-氟丙酰胺基） -4-甲氧苯基] (3，， 4，， 5，-三甲氧基苄基） 酮 （25) 的合成
以 3-氨基 -4-甲氧基苯甲酸、 2-氟丙酰氯和 3， 4， 5-三甲氧基苄基镉为原料, 按照实施例 37类似方法， 合成得到化合物 25 (收率 57%)
1H NMR (CDC13, δ ) 1.3 (d, 3H, CH3) , 3.2(s,2H,-COCH2), 3.8 (s, 9H, 4，,5，,6，-OCH3), 3.95(s, 3H, 4-OCH3)， 4.5(q, IH, CHF), 6.44(s, 2H, 2，,6，-H), 6.98(d, IH, 5-H), 7.16(br, IH, 3-NHCO), 7.4(dd, IH, 6-H), 7.9(br, IH, 1-CONH), 9.2(d, IH, 2-H)
<实施例 39>、 1- (3， -丙酰胺基 -4-甲氧苯基） -2- (3"， 4"， 5，，-三甲氧基苯基） 乙醇（32) 的合成
将实施例 38所得产物 25溶于甲醇中，加入适量 NaBH4还原，原料消失后终 止反应， 分离得到目标化合物 32 (收率 86)。
1H NMR (DMSO-de, δ) 1.03 (t, 3H, CH3) , 2.5(q, 2H, CH2), 3.8 (s, 9H, 4，,5，,6，-OC¾), 3.95(s, 3H, 4-OCH3), 4.4(d,2H，2-C¾), 5.0(t,lH,l-CH), 6.7(s, 2H, 2",6"-H), 7.3 (d, 1H, 5，-H), 7.4(s,lH,3'-NHCO), 7.9(dd, 1H, 6，-H), 9.2(s， 1H, 2，-H) 按照实施例 37的类似方法， 合成得到的化合物包括 13、 16、 20、 28。
〈实施例 40〉、 hA3G上调活性筛选实验
取细胞进行培养， 待细胞长满培养瓶后， 弃旧培养基， 用消化液消化。待细 胞变圆， 弃消化液， 立即加入培养基， 用吸管轻轻吹打瓶底， 使细胞完全脱离瓶 底且使之分散为单细胞悬液。血球计数板计数后， 取细胞悬液接种于培养皿，用 于进行细胞转染。 将含有转染质粒和转染试剂的培养基轻轻混匀， 室温孵育后， 加到细胞培养上清中， 培养一段时间。然后吸去旧的培养基， 用消化液消化， 弃 消化液， 立即加入培养基， 轻轻吹打， 使细胞分散为单细胞悬液。血球计数板计 数后， 接种。
化合物样品： 取纯品化合物溶到 DMS0中， 加水倍比稀释， 取
稀释液作用于细胞体系。
在细胞培养上清中加入不同浓度的检测样品。继续培养后，吸去旧的培养基， 用磷酸缓冲液 （PBS) 吹打细胞， 直至细胞完全脱离。
将细胞悬液转移到黑板中， 检测荧光强度， 激发波长^.485皿， 检测波长为 520nm。 测量两次取平均值。
测定的荧光强度减去空白对照组的数值作为各组 YFP荧光强度数值。 相对荧光强度 =实验组荧光强度 I阳性组荧光强度 X 100%
降解抑制率 = (样品实验组一阴性对照组） I (阳性组一阴性对照组） X
100%
筛选结果列入表 1。
<实施例 41>、 抑制 HIV-1 活性测定实验
在 96孔细胞培养中加入 8个不同稀释浓度的表 2化合物样品的 DMSO溶液 和阳性对照药 AZT (齐多呋啶， 0.15ng/ml) DMSO溶液， 每个稀释度重复 2孔， 设细胞对照;再将 2χ105细胞 /ml 100 μ 1接种于含药 96孔细胞培养板内。置 37°C、 5%C02和饱和湿度培养箱内培养，每天观察细胞病变。按 HIV-1 P24抗原试剂盒 提供的操作步骤，测定加药后第 4天（96小时）细胞培养上清 HIV-1 P24抗原含 量， 计算药物对病毒的抑制活性， 结果列入表 2。

Claims

权利要求
1、 一组胺基苯酰衍生物， 其结构如式 （I)所示:
Figure imgf000029_0001
(I)
其中:
Ri代表： 氢， 连接于苯环的一个或多个硝基、 卤素、 氰基、 酯基、 酰胺基、 羟基、巯基、取代或未取代的低级烷基、低级烷氧基或芳基氧基、低级烷硫基或 芳基硫基、 氨基或取代的氨基等；
R2， R3可以相同也可以不同， 代表： 氢、 低级烷基、 羰基或磺酰基；
X代表： 0、 S、 NH、 NR5、 C¾或 CH ;
Y代表： C、 S或 so;
R4 、 R5代表： 氢、 低级烃基、 羟基、 芳烃或取代的芳烃。
2、制备权利要求 1所述式（I)化合物的方法， 其具体反应步骤是： 将保护 的或酰化后的 A与 1-羟基苯并三唑、 Ν,Ν'-二异丙基碳二亚胺，按摩尔比 1:0.5~3 混合溶于 Ν,Ν'-二甲基亚砜中， 约半小时后加入 Β， 室温下反应 24小时， 产物用 柱层析分离纯化。
Figure imgf000029_0002
M: halogen or OH
A B (I) 其中，
x=o、 s或丽；
Y=C、 s或 so;
Ri > ， R3及 同权利要求 1。
3、 权利要求 1所述化合物在药学上可接受的盐。
4、 权利要求 1所述化合物的药物组合物， 以其含有治疗有效量的上述化合 物为活性成分， 与一种或多种药学上可接受的载体所组成。
5、 权利要求 1所述化合物在制备抗病毒药物中的应用。
6、 权利要求 3所述药学上可接受的盐在制备抗病毒药物中的应用。
7、 权利要求 4所述药物组合物在制备抗病毒药物中的应用。
PCT/CN2009/001094 2008-09-28 2009-09-28 一组氨基苯酰衍生物及其制备方法和应用 WO2010037271A1 (zh)

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